Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas.

Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas.

J Clin Endocrinol Metab. 2018 Feb 21;:

Authors: Hage M, Viengchareun S, Brunet E, Villa C, Pineau D, Bouligand J, Teglas JP, Adam C, Parker F, Lombès M, Tachdjian G, Gaillard S, Chanson P, Tosca L, Kamenický P

Abstract
Purpose: The molecular pathogenesis of growth hormone (GH)-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation-negative somatotroph tumors.
Experimental Design: We performed cytogenetic profiling of pituitary adenomas obtained from 39 acromegalic patients and 4 patients with sporadic gigantism by using array comparative genomic hybridization (array-CGH) analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH).
Results: Based on copy-number profiles, we found two groups of adenomas: a low copy number alteration group (CNA: <12% of genomic disruption, 63% of tumors) and a high CNA group (24-45% of genomic disruption, 37% of tumors). Arm-level CNAs were the most common abnormalities. GNAS mutation-positive adenomas belonged exclusively to the low CNA groups, whereas a subgroup of GNAS mutation-negative adenomas had a high degree of genomic disruption. We detected chromothripsis-related CNA profiles in the two adenoma samples, from an AIP mutation-positive acromegalic patient and a patient with sporadic gigantism. RNA sequencing of these two samples identified 17 fusion transcripts, most of which resulted from chromothripsis-related chromosomal rearrangements. DNA FISH analysis of these samples demonstrated a subclonal architecture with up to six distinct cell populations in each tumor.
Conclusion: Somatotroph pituitary adenomas display substantial inter- and intratumor DNA copy-number heterogeneity, as revealed by variable CNA profiles and complex subclonal architecture. The extensive cytogenetic burden in a subgroup of GNAS mutation-negative somatotroph adenomas points to an alternative tumorigenic pathway linked to genomic instability.

PMID: 29474559 [PubMed - as supplied by publisher]

http://ift.tt/2CiIy5t